Caffeine Withdrawal and Relief of Abstinence Symptoms by Caffeine
- Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use

VI. Caffeine Withdrawal and Relief of Abstinence Symptoms by Caffeine

A. Animal Studies on Caffeine Withdrawal

There are few animal studies on caffeine withdrawal. Caffeine withdrawal induces a 2-fold decrease in rat locomotor activity. This effect lasts for about 4 days and is dose-dependent and maximal on the second day (Griffiths and Woodson, 1988c

B. Human Studies

Humans can experience a variety of withdrawal symptoms. These include weariness, apathy, weakness and drowsiness, headaches, anxiety, decreased motor behavior, increased heart rate, and increased muscle tension and, occasionally, tremor, nausea, vomiting, and flu-like feelings (Griffiths et al., 1990

Anecdotal reports on complaints induced by caffeine withdrawal go far back into the last century. The first controlled study was carried out by Dreisbach and Pfeiffer (1943), who gradually increased the dose of caffeine across 7 days up to 850 mg/day and then substituted this medication with placebo capsules. Fatigue, disinclination to work, mental depression, and headache appeared in most subjects. Headache was alleviated by reinstitution of caffeine but hardly by conventional analgesics. This may be related to changes in blood flow. Caffeine has central vasoconstrictive properties, which lead to a 20 to 30% decrease in cerebral blood flow in humans and in animals. This decrease can be achieved in humans after the absorption of 250 mg of caffeine (Mathew and Wilson, 1985; Cameron et al., 1990). Thus, blood flow velocity in the middle cerebral, posterior cerebral, and basilar arteries is increased during withdrawal, and decreased within 30 min after intake of caffeine, returning to baseline values after 2 h (Couturier et al., 1997).

Withdrawal symptoms generally begin about 12 to 24 h after sudden cessation of caffeine consumption and reach a peak after 20 to 48 h. However, in some individuals, these symptoms can appear within only 3 to 6 h and can last for 1 week (Barone and Roberts, 1984; James, 1991; Nehlig and Debry, 1994; Phillips-Bute and Lane, 1998). Thus, even a short abstinence, equivalent to missing the morning cup of coffee, can lead to significant unpleasant effects (Phillips-Bute and Lane, 1998). There were generally more complaints in the afternoons than in the mornings. All complaints tended to be as severe or even more severe on the second than on the first day of abstinence, but had nearly vanished by the third day. Most complaints were correlated with the headache reports, suggesting that they were secondary to headache. Furthermore, in a group that alternated between 1 day of caffeine consumption and 2 caffeine-free days, the complaints decreased from the first period of abstinence to the next and vanished almost completely by the third one, demonstrating that more than 1 day of previous caffeine exposure is needed to induce withdrawal symptoms (Höfer and Bättig, 1994a,b). The syndrome is further probably specifically due to the discontinuation of caffeine intake, because it persisted regardless of the increased consumption of over-the-counter analgesics that closely paralleled the intensity of the headache complaints.

A great number of laboratory studies, particularly by the Griffiths group (Griffiths and Woodson, 1988a; Griffiths and Mumford, 1995; Schuh and Griffiths, 1997), has since then confirmed the withdrawal syndrome using doses of caffeine ranging from 0.2 to 1 g daily. There are no reliable effects on social behavior during withdrawal (Comer et al., 1997). This can be contrasted to the major effect on performance and social behavior upon withdrawal from other drugs.

Warburton and Thompson (1994) analyzed data from a life-style survey on 9000 subjects with respect to a number of different behavioral and personality attributes, including coffee drinking and headache. Headache was reported more frequently by women than men and less with increasing age. The relation to coffee drinking was biphasic with the fewest reports by moderate drinkers (3-4 cups/day) and more reports by both drinkers of more and of less coffee. On the other hand, headache was positively related to alcohol consumption. One might expect, from the animal data cited above, that heavy caffeine users would experience stronger withdrawal symptoms than light users. In a field study including 60 males and 40 females (Höfer and Bättig, 1994a,b) about half of the subjects subjected to withdrawal experienced moderate headache and about 20% more severe headache. However, the subjects with headache did not differ from those without headaches with respect to the magnitude of their caffeine consumption.

A lack of relationship between withdrawal symptoms and the quantity of caffeine ingested daily is also reported in another study: withdrawal symptoms were found in subjects with a daily caffeine intake ranging from 129 mg (1-2 cups of coffee) to 2548 mg (20-30 cups of coffee) (Strain et al., 1994).

Several investigators studied the effects of caffeine withdrawal on objective measures of performance, such as speed of finger tapping (Bruce et al., 1991; Strain et al., 1994) or reaction times (Rizzo et al., 1988) in users and nonusers of coffee, and failed to see differences, although performance decreased in the users when they abstained from coffee. In a more recent study, however, brief deprivation of caffeine did not affect psychomotor performance in several tests despite the fact that there were major effects on activity and many subjects experienced headaches (Lane, 1997).

Withdrawal symptoms have been reported in newborns whose mothers were heavy coffee drinkers during pregnancy. These infants display irritability, high emotivity, and even vomiting. Symptoms begin at birth and spontaneously disappear after a few days (McGowan et al., 1988). Caffeine withdrawal may also occur in schoolchildren who largely obtain their caffeine from soft drinks (Goldstein and Wallace, 1997). Furthermore, these effects tended to be larger in children with a high consumption, even though this high consumption would correspond to consumption of only a few cups of coffee daily by adults (Goldstein and Wallace, 1997).

C. Effect of Caffeine on Withdrawal Symptoms

In their pioneering study on caffeine withdrawal, Dreisbach and Pfeiffer (1943)

It has been suggested that the studies showing an improved psychomotor performance following caffeine are all flawed because they have not taken caffeine withdrawal into account (James, 1994, 1995). Whereas the point is well taken, it may not explain all the data. For example, it has been pointed out 1) that caffeine withdrawal of the magnitude usually seen in the cited studies above does not lead to a marked decrease in psychomotor performance (Rogers et al., 1995) and 2) that caffeine appears to have effects in such tasks even in the absence of any real withdrawal (Rogers et al., 1995; Warburton, 1995).

Heavy consumers of coffee show a preference for coffee containing caffeine if they have been drinking this type of coffee for 1 week or more, whereas subjects who have been drinking decaffeinated coffee will choose either decaffeinated or caffeine-containing coffee (Griffiths et al., 1986a; Stern et al., 1989). Indeed, caffeine content influences coffee drinking (Kozlowski, 1976; Griffiths et al., 1986b) and caffeine alone is able to reverse withdrawal syndromes induced by caffeinated coffee cessation (Goldstein and Kaizer, 1969; Goldstein et al., 1969; Griffiths et al., 1986a). Caffeine doses as low as 100 mg were associated with alertness, well-being, sociability, willingness to work, energy, and self-confidence (Griffiths et al., 1990). The beneficial effects, derived or expected, of caffeine consumption on mood or performance would indeed seem to incite people to drink coffee or caffeine-containing beverages (Kuznicki and Turner, 1986; Richardson et al., 1995).

The risk of caffeine withdrawal headache has recently also been recognized for hospitalized patients who are required to fast before operations. Nikolajsen et al. (1994) examined perioperative headache in 219 patients who fasted from midnight before the surgical intervention. The odds ratio for patients to develop postoperative headache amounted to 5.0 for those consuming more than 400 mg/day caffeine and to 3.7 for those operated after noon on the following day. The frequency of pre- and perioperative headaches is strongly correlated with the duration of fasting and the daily consumption of caffeine (Fennelly et al., 1991; Nikolajsen et al., 1994) and is reduced in individuals who drank caffeine or got substitutive caffeine tablets on the day of the surgery (Weber et al., 1993; Hampl et al., 1995). Therefore, it was supported by three studies that the numerous healthy patients who drink caffeine beverages daily and are undergoing minor surgical procedures should be permitted to ingest preoperative caffeine (Weber et al., 1993; Nikolajsen et al., 1994) or even be given prophylactic i.v. caffeine (Weber et al., 1997).

Subjects who had withdrawal headaches and drowsiness were 2.3 to 2.6 times more likely to self-administer caffeinated coffee (Hughes et al., 1993). Several variables (e.g., average caffeine intake) did not predict caffeine self-administration or withdrawal. In another study (Mitchell et al., 1995), the effects of complete or partial caffeine deprivation on withdrawal symptomatology and self-administration of coffee in caffeine-dependent coffee drinkers were examined. Caffeine deprivation was manipulated by administering capsules containing 0%, 50%, or 100% of each subject's daily caffeine intake (complete, partial, and no deprivation conditions). Caffeine withdrawal symptomatology was measured using self-report questionnaires. Caffeine self-administration was measured using: 1) the amount of coffee subjects earned on a series of concurrent random-ratio schedules that yielded coffee and money reinforcers; 2) the amount of earned coffee they consumed. Caffeine withdrawal symptoms occurred reliably following complete caffeine deprivation, although not in the partial deprivation condition. Caffeine self-administration was not related to deprivation condition, indicating that caffeine withdrawal symptomatology is not necessarily associated with increased caffeine consumption.

A different conclusion was, however, drawn from a recent study on 20 subjects who were moderate consumers of caffeine (average daily intake 379 mg) (Schuh and Griffiths, 1997). Using saliva measurements, it was ascertained that the subjects generally complied with an admonition to refrain from caffeine during the study. They were then asked to rate their subjective impression of the of randomly assigned placebo or caffeine capsules and to assign a cash value to receiving the same type of capsule again. The symptoms of headache, feeling "worn out" and experiencing "flu-like symptoms" were, as expected, higher in the subjects that received placebo than in those that received caffeine. Conversely, caffeine capsules were associated with subjective alertness, well-being, and symptoms of stomach upset (Schuh and Griffiths, 1997). Importantly, the subjects chose caffeine and were willing to forfeit money to avoid receiving placebo. Because this behavior correlated with the symptom of headache, the authors conclude that choice of coffee is potently controlled by avoiding withdrawal. In fact, in this study, avoiding withdrawal was a stronger controller of caffeine intake than were the positive effects of caffeine.

This conclusion was later confirmed in another well-controlled study (Garrett and Griffiths, 1998).

observed that caffeine was highly efficient in relieving withdrawal headache. The same observation has since been made in many other studies. This raises the question: To what extent do people consume coffee in order to avoid or terminate headache? Cines and Rozin (Cines and Rozin, 1982) did a study on the different aspects of liking coffee in 180 adult coffee drinkers. Liking coffee flavor was linked mostly to the hot coffee and correlated with the pharmacological effects of the morning coffee. Coffee liking was scored higher by those subjects who indicated that coffee gives a good feeling, calms the nerves, stimulates, helps thinking and vigilance, and last but not least reduces or prevents headache. Volunteers asked to discriminate between caffeine and placebo mentioned tiredness and headache as the most important cues for the detection of placebo (Evans and Griffiths, 1992).; Silverman et al., 1992; Nehlig and Debry, 1994; Höfer and Bättig, 1994a,b; Strain et al., 1994; Griffiths and Mumford, 1995; Schuh and Griffiths, 1997). There are also several reports on caffeine abstinence and postoperative headaches (Fennelly et al., 1991; Weber et al., 1993; Nikolajsen et al., 1994). Mathew and Wilson (1985) reported that, in high but not in low caffeine consumers, abstinence was followed by marked increases of blood flow in the frontal lobes. Two studies insisted that caffeine withdrawal should be included in the list of diagnoses recognized by the American Health System (DSM-IV and ICD-10) (Hughes et al., 1992b; Strain et al., 1994).; Nehlig and Debry, 1994). Caffeine withdrawal also affects the effect of caffeine on cerebral electrical stimulation in the rat (Mumford et al., 1988). Withdrawal of chronic caffeine intake in rats results in disruptions in operant responding (Carney, 1982; Mumford et al., 1988) and decreases in locomotor activity (Holtzman, 1983; Finn and Holtzman, 1986), effects that last from one to several days. The magnitude and duration of caffeine withdrawal appears to be a direct function of the amount of caffeine that has been consumed daily. Disruption of operant behavior is also observed in the monkey after caffeine deprivation but is less pronounced than after phencyclidine or cocaine deprivation (Carroll et al., 1988). Withdrawal of caffeine after continuous infusion at the level of 190 mg/kg/day to mice caused a marked decrease in locomotor behavior, which gradually returned to normal after the first few days (Kaplan et al., 1993; Nikodijeviç et al., 1993). In the withdrawal phase, the peak stimulatory effect was slightly shifted from 30 to about 20 mg/kg (Nikodijeviç et al., 1993) indicating a supersensitivity to the depressant actions of caffeine. Low doses of caffeine also restored the lowered locomotion to normal.

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